Clinical Pharmacokinetics of Troglitazone

Abstract

Troglitazone is a new thiazolidinedione oral antidiabetic agent approved for use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Food increases the absorption by 30 to 80%. The pharmacokinetics of troglitazone are linear over the clinical dosage range of 200 to 600 mg once daily. The mean elimination half-life ranges from 7.6 to 24 hours, which facilitates a once daily administration regimen. The pharmacokinetics of troglitazone are similar between patients with type 2 diabetes and healthy individuals. In humans, troglitazone undergoes metabolism by sulfation, glucuronidation and oxidation to form a sulfate conjugate (M1), glucuronide conjugate (M2) and quinone metabolite (M3), respectively. M1 and M3 are the major metabolites in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacokinetics of troglitazone and its 2 major metabolites. In patients with hepatic impairment the plasma concentrations of troglitazone, M1 and M3 increase by 30%, 4-fold, and 2-fold, respectively. Cholestyramine decreases the absorption of troglitazone by 70%. Troglitazone may enhance the activities of cytochrome P450 (CYP) 3A and/or transporter(s) thereby reducing the plasma concentrations of terfenadine, cyclosporin, atorvastatin and fexofenadine. It also reduces the plasma concentrations of the oral contraceptive hormones ethinylestradiol, norethindrone and levonorgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, glibenclamide (glyburide) or paracetamol (acetaminophen). There is no pharmacodynamic interaction between troglitazone and warfarin or alcohol (ethanol). Pharmacodynamic modelling showed that improvement in fasting glucose and triglyceride levels increased with dose from 200 to 600 mg. Knowledge of systemic troglitazone exposure within a dose group does not improve the prediction of glucose lowering response or adverse effects beyond those based on the administered dose.

Troglitazone and liver injury: In search of answers

“…mol/L) was approximately 12% of the CMax for TGZ ϩ M1 ϩ M3. 63 This indicates a very efficient metabolism of TGZ by the liver, supporting the notion that hepatic TGZ in humans is in equilibrium with plasma TGZ. 59 The peak level occurs approximately 4 hours after taking TGZ, and the plasma concentration drops progressively from 4 to 24 hours, which would also decrease the liver concentration concomitantly.…”

“…64,65 Moreover, because TGZ is tightly bound to albumin in plasma (95%-99.8%), only 0.2% to 5% is available as free plasma TGZ capable of a steady-state equilibrium with hepatocytes. 59,63 It has been speculated that TGZ levels in the livers of patients with alcohol-induced liver disease and NASH should be higher than in normal individuals, leading to greater rates of liver injury in these patients. 3 However, this hypothesis is not supported by the available experimental data.…”

“…Furthermore, TGZ toxicity to hepatocytes cultured without albumin, which artificially enhances the TGZ bioavailability by up to approximately 500-fold, 59 was markedly reduced when albumin was added to the media. 123 TGZ was cytotoxic to cryopreserved human hepatocytes, judging by the decrease in cellular adenosine triphosphate, 125 but the validity of these results is unclear because of the following issues: i) cryopreservation is associated with a loss of hepatocyte viability 126,127 ; ii) TGZ induced hepatocyte toxicity at concentrations approximately 20-fold greater than that achieved therapeutically in the liver 58,63,64 ; iii) the absence of albumin in the culture media increases TGZ bioavailability 20-to 500-fold 59,64 ; and iv) rosiglitazone also induced cytotoxicity, albeit with a higher median effective concentration Predictive model systems for TGZ-induced liver toxicity could include highly differentiated human hepatocytes, cocultured with other liver cells (endothelial, macrophages, or stellate cells), given their modulatory role on hepatocyte injury and survival, 128,129 as well as mice expressing humanized xenobiotic responses. 96 …”

Comparative Effects of Thiazolidinediones on in Vitro P450 Enzyme Induction and Inhibition

“…These data indicate that at the doses administered, rosiglitazone and pioglitazone are not significant inducers or inhibitors of CYP3A4 or CYP2C9. Troglitazone induced CYP3A4 activity as exemplified by clinical interactions with atorvastatin, simvastatin, oral contraceptives, cyclosporine, and terfenadine (Kaplan et al, 1998;Loi et al, 1999) and did not affect the CYP2C9-mediated metabolism of warfarin or glyburide (Rezulin package insert).…”

Involvement of Organic Anion Transporting Polypeptides in the Transport of Troglitazone Sulfate: Implications for Understanding Troglitazone Hepatotoxicity

“…Although there have been several studies investigating the mechanisms of the hepatotoxicity, including apoptotic hepatocyte death and intrahepatic cholestasis, the details remain to be clarified (Gitlin et al, 1998;Kostrubsky et al, 2000;Yamamoto et al, 2001). In humans, the metabolism of troglitazone involves sulfation, glucuronidation, and oxidation (Kawai et al, 1997;Loi et al, 1999). The sulfate conjugate (M-1; Fig.…”